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BACKGROUND The transition to dolutegravir-containing antiretroviral therapy (ART) in low- and middle-income countries (LMICs) was complicated by an initial safety signal in May 2018 suggesting that exposure to dolutegravir at conception was possibly associated with infant neural tube defects. On the basis of additional evidence, in July 2019, the World Health Organization recommended dolutegravir for all adults and adolescents living with HIV. OBJECTIVE To describe dolutegravir uptake and disparities by sex and age group in LMICs. DESIGN Observational cohort study. SETTING 87 sites that began using dolutegravir in 11 LMICs in the Asia-Pacific; Caribbean, Central and South America network for HIV epidemiology (CCASAnet); and sub-Saharan African regions of the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. PATIENTS 134��672 patients aged 16 years or older who received HIV care from January 2017 through March 2020. MEASUREMENTS Sex, age group, and dolutegravir uptake (that is, newly initiating ART with dolutegravir or switching to dolutegravir from another regimen). RESULTS Differences in dolutegravir uptake among females of reproductive age (16 to 49 years) emerged after the safety signal. By the end of follow-up, the cumulative incidence of dolutegravir uptake among females 16 to 49 years old was 29.4% (95% CI, 29.0% to 29.7%) compared with 57.7% (CI, 57.2% to 58.3%) among males 16 to 49 years old. This disparity was greater in countries that began implementing dolutegravir before the safety signal and initially had highly restrictive policies versus countries with a later rollout. Dolutegravir uptake was similar among females and males aged 50 years or older. LIMITATION Follow-up was limited to 6 to 8 months after international guidelines recommended expanding access to dolutegravir. CONCLUSION Substantial disparities in dolutegravir uptake affecting females of reproductive age through early 2020 are documented. Although this disparity was anticipated because of country-level restrictions on access, the results highlight its extent and initial persistence. PRIMARY FUNDING SOURCE National Institutes of Health.

Vortex induced vibration (VIV) is an important phenomenon which appears in flexible structures immersed in a moving fluid. This oscillation is self-sustained and self-limited, but VIV might cause fatigue damage and affect the structure's serviceability.In the present study, the aerodynamics of the flow fields around a static and vertically free-to-oscillate 4:1 rectangular cylinder are analysed by means of 3D LES simulations, adopting the OneEqEddy viscosity model. Integral parameters, pressure distributions, amplitudes of oscillation, coherences and correlations are obtained and compared with the available experimental data. Aiming to ascertain the impact of the boundary conditions and the grid resolution on the accuracy of results, five cases adopting 3 different meshes including two different spanwise discretisations have been considered. When studying the aerodynamics of the cylinder in static conditions, the influence of the spatial discretisation is very limited, and the agreement with experimental data is fairly good. On the other hand, for the free-to-oscillate cylinder, the structural response is dramatically dependent on the spanwise discretisation. The maximum amplitude of the structural response decreases as the mesh resolution increases, providing a closer fit with the experimental data. Also, the spanwise correlation of pressures is studied, finding remarkable differences depending on the level of spatial discretisation.

We propose a local coherence model based on a convolutional neural network that operates over the entity grid representation of a text. The model captures long range entity transitions along with entity-specific features without loosing generalization, thanks to the power of distributed representation. We present a pairwise ranking method to train the model in an end-to-end fashion on a task and learn task-specific high level features. Our evaluation on three different coherence assessment tasks demonstrates that our model achieves state of the art results outperforming existing models by a good margin.

Objective Xpert MTB/RIF is recommended by the World Health Organization (WHO) as the initial tuberculosis (TB) diagnostic test in individuals suspected of HIV-associated TB. We sought to evaluate field implementation of Xpert among a cohort of HIV/TB co-infected individuals, including availability, utilization and outcomes. Design Observational cohort study (patient-level data) and cross-sectional study (site-level Xpert availability data). Methods Data were collected at 30 participating International epidemiologic Databases to Evaluate AIDS (IeDEA) sites in 18 countries from January 2012-January 2016. All patients were HIV-infected and diagnosed with TB, either bacteriologically or clinically, and followed until a determination of TB treatment outcome. We used multivariable modified Poisson regression to estimate adjusted relative risk (RR) and 95% confidence intervals for unfavorable TB treatment outcomes. Results Most sites (63%) had access to Xpert, either in the clinic (13%), in the same facility (20%) or offsite (30%). Among 2722 HIV/TB patients included, median age was 35.4 years and 41% were female; BMI and CD4 count were low. Overall, most patients (76%) received at least one TB test; 45% were positive. Only 4% of all patients were tested using Xpert: 64% were Xpert-positive, 13% showed rifampicin (RIF) resistance and 30% were extrapulmonary (EPTB) or both pulmonary-EPTB. Treatment outcomes were mostly favorable (77%) and we found little association between Xpert use and an unfavorable TB treatment outcome (RR 1.25, 95%CI: 0.83, 1.90). Conclusions In this cohort, Xpert utilization was low even though the majority of sites had access to the test. Our findings show the need for expanded implementation and further research exploring barriers to use in low-resource settings.

Discussion forums are an important source of information. They are often used to answer specific questions a user might have and to discover more about a topic of interest. Discussions in these forums may evolve in intricate ways, making it difficult for users to follow the flow of ideas. We propose a novel approach for automatically identifying the underlying thread structure of a forum discussion. Our approach is based on a neural model that computes coherence scores of possible reconstructions and then selects the highest scoring, i.e., the most coherent one. Preliminary experiments demonstrate promising results outperforming a number of strong baseline methods.

Coordinated repression of gene expression by evolutionarily conserved microRNA (miRNA) clusters and paralogs ensures that miRNAs efficiently exert their biological impact. Combining both loss- and gain-of-function genetic approaches, we show that the miR-23~27~24 clusters regulate multiple aspects of T cell biology, particularly helper T (Th) 2 immunity. Low expression of this miRNA family confers proper effector T cell function at both physiological and pathological settings. Further studies in T cells with exaggerated regulation by individual members of the miR-23~27~24 clusters revealed that miR-24 and miR-27 collaboratively limit Th2 responses through targeting IL-4 and GATA3 in both direct and indirect manners. Intriguingly, although overexpression of the entire miR-23 cluster also negatively impacts other Th lineages, enforced expression of miR-24, in contrast to miR-23 and miR-27, actually promotes the differentiation of Th1, Th17, and induced regulatory T cells, implying that under certain conditions, miRNA families can fine tune the biological effects of their regulation by having individual members antagonize rather than cooperate with each other. Together, our results identify a miRNA family with important immunological roles and suggest that tight regulation of miR-23~27~24 clusters in T cells is required to maintain optimal effector function and to prevent aberrant immune responses.

Background Loss to follow-up (LTFU) is viewed as a major challenge in improving retention in HIV treatment. In Vietnam, the reasons for disengagement from clinics and the effect of injection drug use (IDU) on LTFU with unknown outcome (true LTFU) are not well known. Methods Patients receiving antiretroviral therapy (ART) from two HIV clinics in Hanoi were included in this observational study between 2007 and 2012, and followed up every 6 months until the end of 2013. The reasons for disengagement from the clinic, and ART status during imprisonment were investigated in patients with a history of IDU to identify true LTFU. The retention rate at 6-54 months and true LTFU rate were calculated. Cox proportional hazards regression models were performed to identify factors associated with true LTFU. Results There were 1,431 patients, with a follow-up time of 4,371 person-years (median 2.49 years). At the end of the follow-up period, 71 (5.0%) patients died, 79 (5.5%) transferred to other clinics, 16 (1.1%) disengaged from the clinics, and the calculated true LTFU was 45 (3.1%), with 12-month ART retention rate of 95.3% for the entire study population. Imprisonment was the most frequent reason for disengagement from the clinics. True LTFU correlated significantly with low CD4 count and high plasma viral load, but not history of IDU. Conclusion Imprisonment is a major cause of disengagement from HIV care among patients with a history of IDU. © 2015 Matsumoto et al.

One of the current emphases in optimizing anterior cruciate ligament (ACL) reconstructions is closer mimicking the anatomy of the ACL. The aim of Chapter 2 and Chapter 3 is to develop and validate a methodology to quantify the 3-D collagen fiber orientation of ligaments, accurately and at a high resolution. The clinical research question is: how many bundles are present in the human ACL and what should the amount of bundles to be reconstructed. Another current emphasis in improving the ACL reconstruction is graft placement at the original insertion sites of the torn ACL also called - anatomical ACL reconstruction. The aim of Chapter 4 is to develop a new arthroscopic imaging methodology based on fluorescence of collagen molecules to localize the original insertion sites. Another strategy to improve the patient outcome is by healing the torn ACL. In Chapter 5 the aim is to evaluate the effect of the small intestine submucosa bioscaffold (SIS) on the collagen fibrillogenesis in the healing medial collateral ligament. Chapter 6 describes the investigation that aims to improve the efficacy of SIS by remodeling its collagen fibers. The research question was whether this can be achieved through cell-seeding and cyclic stretch. Chapter 7 is a pre-translational study and investigates whether the human ACL has a healing potential by histologic analysis of reattached ACL remnants from patients. The aim in Chapter 8 is to heal the ACL in a goat model and biomechanically evaluate the result. Chapter 9 aims to histologically evaluate the healing ACLs. The final Chapter 10 discusses the findings and implications of this thesis and proposes future studies.